Neurofibromatosis (NF) describes two major human genetic disorders that display autosomal dominant inheritance, involve tumors of the nervous system, and which are distinct clinical entities (Mulvihill, J. J. et al. Ann. Intern. Med. 113:39-52 (1990)). NF1, or von Recklinghausen NF, is more common (incidence of 1/4,000) and is characterized by the highly variable expression of an array of features that include neurofibromas, cafe-au-lait macules, Lisch nodules of the iris, and a predisposition to certain malignant tumors (Riccardi, V. M. et al., N. Engl. J. Med. 305:1617-1627 (1981); Riccardi, V. M. et al., "Neurofibromatosis: Phenotype, Natural History, and Pathogenesis," Johns Hopkins Univ. Press, Baltimore, Md. (1986)). It is caused by defects in a gene on chromosome 17 that has recently been isolated and characterized (Viskochil, D. et al., Cell 62:187-192 (1990); Cawthon, R. M. et al., Cell 62:193-201 (1990); Wallace, M. R. et al., Science 249:183-186 (1990)). The NF1 gene product, neurofibromin, is a large protein with a GAP-related domain and is presumably involved in modulating a signal transduction pathway whose disruption can lead to tumor formation (Ballester, R. et al., Cell 63:851-859 (1990); Buchberg, A. M. et al., Nature 347:291-294 (1990); Xu, G. et al., Cell 62:599-608 (1990); DeClue, J. E. et al., Cell 69:265-273 (1992); Basu, T. N. et al., Nature 356:713-715 (1992)).
In contrast, neurofibromatosis-2 (NF2), which occurs in about 1/40,000 livebirths (Evans, D. G. R. et al., J. Med. Genet. 29:841-846 (1992)), is characterized by bilateral schwannomas that develop on the vestibular branch of the 8th cranial nerve. Pressure from these tumors often causes hearing loss and vestibular symptoms in the second and third decade. Other tumors of the brain, especially meningiomas and schwannomas of other cranial nerves and spinal nerve roots (Martuza, R. L. et al., N. Engl. J. Med. 318:684-688 (1988)), and posterior capsular lens opacities (Kaiser-Kupfer, M. I. et al., Arch. Ophthalmol. 107:541-544 (1989) are commonly present in the young affected adult.
The NF2 gene is highly penetrant. Ninety-five percent of persons with the genotype develop bilateral vestibular schwannomas. NF2 is often more severe than NF1. Teenage or early adulthood onset of multiple slow growing tumors that can gradually cause deafness, balance disorder, paralysis or increasing neurologic problems necessitating repeated surgical procedures, characterizes NF2.
NF2 has been shown to be genetically distinct from NF1 by linkage studies that assigned the NF2 gene to chromosome 22 (Rouleau, G. A. et al., Nature 329:246-248 (1987); Wertelecki, W. et al. N. Engl. J. Med. 319:278-283 (1988); Rouleau, G. A. et al., Am. J. Hum. Genet. 46:323-328 (1990); Narod, S. A. et al., Am. J. Hum. Genet. 51:486-496 (1992)). The tumor types that occur in NF2 can be seen in the general population as solitary, sporadic tumors. Since frequent loss of alleles on chromosome 22 from both sporadic vestibular schwannomas and meningiomas, and from their counterparts in NF2 had been noted previously, the localization of the inherited defect to the same chromosome region suggested that the NF2 locus encodes a recessive tumor suppressor gene (Knudson, A. G. et al., Proc. Natl. Acad. Sci. U.S.A. 68:820-823 (1971)) whose inactivation leads to tumor formation (Seizinger, B. R. et al., Nature 322:644-647 (1986); Seizinger, B. R. et al., Science 236:317-319 (1987); Seizinger, B. R. et al., Proc. Natl. Acad. Sci. U.S.A. 84:5419-5423 (1987).
A number of studies of sporadic tumors and tumors from NF2 patients have provided support for this hypothesis (Couturier, J. et al., Cancer Genet. Cytogenet. 45:55-62 (1990); Rouleau, G. A. et al., Am. J. Hum. Genet. 46:323-328 (1990); Fiedler, W. et al., Genomics 10:786-791 (1991); Fontaine, B. et al., Ann. Neurol. 29:183-196 (1991); Fontaine, B. et al., Genomics 10:280-283 (1991); Bijlsma, E. K. et al., Genes Chromosom. Cancer 5:201-205 (1992); Wolff, R. K. et al., Am. J. Hum. Genet. 51:478-485 (1992)). The combined use of family studies and tumor deletion mapping has progressively narrowed the location of NF2 within the q12 band of chromosome 22, and defined a candidate region in which to search for the NF2 genetic defect (Rouleau, G. A. et al., Am. J. Hum. Genet. 46:323-328 (1990); Wolff, R. K. et al., Am. J. Hum. Genet. 51:478-485 (1992)).